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Energetic Superiority of Two-Center HydrogenBonding Relative To Three-Center HydrogenBonding in a Model System

Jihong Yang and Samuel H. Gellman*

Department of Chemistry, UniVersity of Wisconsin Madison, Wisconsin 53706

ReceiVed May 8, 1998

Hydrogen bonds involving three atoms (often termed bifur-cated) are frequently detected in the crystal structures of smallmolecules1 and biopolymers.2-7 Three-center H-bonding (or theabsence thereof) has been proposed to play an important role inDNA,3 RNA4 and protein5 conformation, small molecule-DNA6

and protein-DNA7 recognition, host-guest complexation,8 andself-assembly.9 Although extensive data are available regardingthe strengths of two-center H-bonds,10 the relative energetic meritsof two-center vs three-center H-bonds have not been probedexperimentally. There are two types of three-center H-bonds,(i) one H atom interacting with two acceptor atoms (which werefer to as an XHY interaction) and (ii) one acceptor atominteracting with two H atoms (which we designate HXH).

Here, we use the equilibrium among different H-bondingpatterns in 1 to monitor the thermodynamic competition among

an XHY three-center interaction and alternative two-centerH-bonds. The folding of1 has been analyzed in dilute nonpolarsolution, so that H-bonding sites either interact intramolecularlyor forego amide-amide H-bonds. Our results show that the XHYthree-center interaction is less energetically favorable than a two-center H-bond.

Depsipeptide 1 has one H-bond donor site and three potentialacceptor sites for intramolecular H-bonds. The ester carbonyl isunlikely to form a 7-membered ring intramolecular H-bond.11

Therefore, we expect three possible intramolecularly H-bondedstates for 1 (Figure 1), 1a, containing a two-center H-bond in a5-membered ring (C5 interaction12), 1b, containing a two-centerH-bond in a 10-membered ring, and 1c, containing an XHY three-center interaction. The conformational equilibrium among 1a-cwas evaluated in dilute CH2Cl2 solution (1 mM). Under these

conditions, H-bonding is directly detectable via IR spectroscopicdata from the N-H stretch region,13,14 and there is no intermo-lecular H-bonding.15

IR data indicate that 1a is the major form in CH2Cl2 solutionat room temperature. The IR spectrum of1 (Figure 1) displaystwo absorption maxima in the N-H stretch region, at 3401 and3331 cm-1. Assignment of these bands is aided by IR data forreference compounds 216,17 and 3.18 Glycine derivative 2 is almostcompletely locked into the 5-membered ring H-bond under theseconditions, displaying only one N-H stretch maximum, at 3406cm-1 (Figure 1). Amide 2 also displays a very small shoulder atca. 3447 cm-1, which corresponds to non-H-bonded N-H.Depsipeptide 3 folds largely to the 10-membered ring H-bondedform, as indicated by the dominant N-H stretch band at 3334cm-1; the minor band at 3456 cm-1 indicates a small populationof non-H-bonded N-H (Figure 1). For 1, the larger band at 3401cm-1 is assigned to folding pattern 1a. The smaller band at 3331cm-1 is consistent with folding pattern 1b, containing only a 10-membered ring H-bond, because of the spectroscopic similarityto 3. The XHY three-center interaction (1c) might also contribute

(1) (a) Baur, W. H. Acta Crystallogr. 1965, 19, 909. (b) Taylor, R.; Kennard,O.; Versichel, W. J. Am. Chem. Soc. 1982, 104, 244. (c) Jeffrey, G. A.; Mitra,J. J. Am. Chem. Soc. 1982, 104, 5546. (d) Reutzel, S. M.; Etter, M. C. J.Phys. Org. Chem. 1992, 5, 44.

(2) Baker, E. N.; Hubbard, R. E. Prog. Biophys. Mol. Biol. 1984, 44, 97.(3) (a) Nelson, H. C. M.; Finch, J. T.; Luisi, B. F.; Klug, A. Nature 1987,

330, 221. (b) Coll, M.; Frederick, C. A.; Wang, A. H.-J.; Rich, A. Proc. Natl.Acad. Sci. U.S.A. 1987, 84, 8385. (c) For different conclusions about the roleof three-center H-bonds in DNA conformation, see: Fritsch, V.; Westhof, E.J. Am. Chem. Soc. 1991, 113, 8271.

(4) Allain, F. H.-T.; Varani, G. J. Mol. Biol. 1995, 250, 333.

(5) (a) Sundaralingam, M.; Sekharudu, Y. C. Science 1989, 244, 1333. (b)Preissner, R.; Egner, U.; Saenger, W. FEBS Lett. 1991, 288, 192.(6) (a) Kopka, M. L.; Yoon, C.; Goodsell, D.; Pjura, P.; Dickerson, R. E.

J. Mol. Biol. 1985, 183, 553. (b) Jain, S.; Zon, G.; Sundaralingam, M.Biochemistry 1989, 28, 2360.

(7) Aggarwal, A. K.; Rodgers, D. W.; Drottar, M.; Ptashne, M.; Harrison,S. C. Science 1988, 242, 899.

(8) Askew, B.; Ballester, P.; Buhr, C.; Jeong, K. S.; Jones, S.; Parris, K.;Williams, K.; Rebek, J. J. Am. Chem. Soc. 1989, 111, 1082.

(9) Conn, M. M.; Rebek, J. Chem. ReV. 1997, 97, 1647 and referencestherein.

(10) (a) Joesten, M. D.; Schaad, L. J. Hydrogen Bonding; Marcel Dekker:New York, 1974. (b) Arnett, E. M.; Mitchell, E. J.; Murty, T. S. S. R. J. Am.Chem. Soc. 1974, 96, 3875.

(11) (a) Boussard, G.; Marraud, M. Biopolymers 1981, 20, 169. (b) Gallo,E. A.; Gellman, S. H. J. Am. Chem. Soc. 1993, 115, 9774.

(12) (a) Avignon, M.; Huong, P. V.; Lascombe, J.; Marraud, M.; Neel, J.Biopolymers 1969, 8, 69. (b) Burgess, A. W.; Scheraga, H. A. Biopolymers1973, 12, 2177. (c) Ashish; Kishore, R. Tetrahedron Lett. 1997 38, 2767.(13) (a) Tsuboi, M.; Shimanouchi, T.; Mizushima, S. J. Am. Chem. Soc.1959, 81, 1406. (b) Maxfield, F. R.; Leach, S. J.; Stimson, E. R.; Powers, S.P.; Scheraga, H. A. Biopolymers 1978, 17, 2507.

(14) (a) Gellman, S. H.; Dado, G. P.; Liang, G.-B.; Adams, B. R. J. Am.Chem. Soc. 1991, 113, 1164. (b) For related work, see: Gung, B. W.; Zhu,Z. J. Org. Chem. 1996, 61, 6482.

(15) Relevant data may be found in the Supporting Information.(16) Cung, M. T.; Marraud, M.; Neel, J. In Proceedings of the 5th Jerusalem

Symposium on Quantum Chemisty and Biochemistry; Bergman, E.; Pullman,B., Eds.; Israel Academy of Sciences and Humanities, Jerusalem, 1973, pp69ff.

(17) Dado, G. P.; Gellman, S. H. J. Am. Chem. Soc. 1993, 115, 4228.(18) (a) Boussard, G.; Marraud, M.; Neel, J.; Maigret, B.; Aubry, A.

Biopolymers 1977, 16, 1033. (b) Aubry, A.; Protas, J.; Boussard, G.; Marraud,M. Acta Crystallogr. 1974 B30, 1992.

Figure 1. N-H stretch region FT-IR data for 1 mM samples ofcompounds 1-4 in CH2Cl2 at rm temp, after subtraction of the spectrumof pure CH2Cl2 (nominal resolution 2 cm-1). Data acquired on a Nicolet740 spectrometer as previously described.14a,17 (1) Maxima at 3401 and3331 cm-1, (2) maximum at 3406 and shoulder at ca. 3447 cm-1, (3)maxima at 3456 and 3334 cm-1.

9090 J. Am. Chem. Soc. 1998, 120, 9090-9091

S0002-7863(98)01604-7 CCC: $15.00 1998 American Ch emical SocietyPublished on Web 08/21/1998

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to this lower energy band, since it has been reported in one casethat a two-center H-bond and a comparable XHY three-centerinteraction give rise to similar N-H stretch bands.19 We assumethat 1c would not show an N-H stretch band above 3370 cm-1,because the 10-membered ring H-bond alone (as in 3) gives riseto a band at lower energy. This assumption is supported by thebehavior of1 in the solid state. The crystal structure of115 showsan intermolecular XHY three-center interaction; the NH isinvolved in a 5-membered ring H-bond (HO ) 2.34 ,N-HO angle ) 101) and in an intermolecular H-bond

(HO ) 2.11 , N-HO angle ) 161). Solid 1 has an N-Hstretch IR band at 3236 cm-1.20

The data discussed above indicate that the conformationcontaining the C5 two-center H-bond (1a) is superior to theconformation containing the three-center XHY interaction (1c),and to the conformation containing the 10-membered ring H-bond(1b), in terms of Gibbs free energy at room temperature. Toprovide insight into enthalpic and entropic relationships, wecarried out variable temperature IR studies. We have previouslyshown that N-H stretch region IR data can be used to quantifyintramolecular H-bonding equilibria if one can identify referencecompounds that provide integrated extinction coefficients forappropriate IR bands.21

The room-temperature N-H stretch data for 1 suggest that thefolding of this molecule can be analyzed in terms of a two-state

model (eq 1), in which one state has only the 5-membered ring

H-bond (1a; band at 3401 cm-1) and the other state has the 10-membered ring H-bond and/or the XHY three-center interaction(1b and/or 1c, band at 3331 cm-1). As the temperature is lowered,the intensity of each band increases, but the proportions of thetwo bands remain similar.15 We employed variable temperaturedata for reference compound 2 to estimate the integrated extinctioncoefficient for the band assigned to N-H involved in a 5-mem-bered ring H-bond. Mathematical decomposition methods wereused to isolate the band centered near 3406 cm-1 in the spectrumof 2 at various temperatures, and the integrated absorbance ofthis band was assumed to arise from the total concentration of2.(Since there is a tiny absorbance at higher wavenumber for 2,this approach slightly overestimates the molar integrated extinctioncoefficient for the 5-membered ring H-bonded band; however,this small error should not influence our conclusions.) Thepopulation of folding pattern 1a was then estimated by applyingthe temperature-dependent integrated extinction coefficient derivedfrom 2 to the band centered near 3406 cm-1, isolated by spectraldecomposition, in the IR spectrum of1 at several temperatures.15

According to this analysis, the population of1a does not changebetween 220 and 300 K. In light of the vant Hoff relationship[ln Keq ) (-H/RT) + (S/R)], this temperature independenceimplies that the two states in eq 1 are isoenthalpic and that 1a isheavily populated (ca. 80%) because of an entropic advantage.Thus, the conformation containing the three-center XHY interac-tion available to 1, if it forms at all, is no more favorable

enthalpically than the alternative conformations containing two-center H-bonds. In other words, once the XH interaction isformed, adding the HY interaction produces no significantenthalpic improvement.

Since the 10-membered ring H-bond is almost fully formed inreference compound 3 at all temperatures, the dominance of 1aimplies that formation of the 5-membered ring H-bond in 1interferes with formation of the 10-membered ring H-bond. Thisinterference is remarkable because the H-bond in the smaller ringis geometrically inferior and, therefore, presumably energetically

inferior2,21 to the H-bond in the larger ring. (The 5-memberedring interaction requires a pronounced nonlinearity of theN-HO angle, while the 10-membered ring interaction allowsan N-HO angle near 180.) The energetic preference mani-fested in 1 for a conformation containing a two-center H-bondover a conformation containing a three-center XHY interactionmay represent a general trend because the dominant H-bond in 1has a poor geometry (i.e., two-center H-bonds with bettergeometries than allowed by the 5-membered ring should also besuperior to three-center XHY interactions).

It is important to note that the stability of a conformationcontaining an intramolecular H-bond is not necessarily related tothe stability of the H-bond itself.14a,22 Specifically, the extensive5-membered ring H-bonding in 1 and reference compound 2 isprobably nota result of the H-bond itself but rather a manifestation

of other factors, including antiparallel alignment of adjacentdipoles, avoidance of allylic-type strain, and minimal entropiccost. None of these other factors in the 5-membered H-bondedring should affect formation of the 10-membered ring H-bondavailable to 1; therefore, the equilibrium among 1a, 1b, and 1cshould reflect the influence of one two-center interaction on theother. The dominance of1a indicates that the three-center XHYinteraction is less favorable than a two-center H-bond.

Our data indicate that there is no enthalpic advantage to formingan XHY three-center interaction in 1, relative to forming a two-center H-bond, even when failure to form the three-center H-bondmeans that a H-bond acceptor remains free of interaction with agood donor site. The behavior of1 may be rationalized at leastpartially by the secondary interaction hypothesis of Jorgensenet al.23 (i.e., for 1c, competition between the electrostatic attraction

of the amide proton for the two amide oxygen atoms and theelectrostatic repulsion between the oxygen atoms). The Jorgensenhypothesis23 and subsequent modifications24 predict that XHYthree-center interactions would become favorable if both acceptorsoccurred in the same molecule and were rigidly held in the properarrangement.25 Our results suggest that XHY three-center H-bonds observed in crystal structures of flexible molecules,1-7 orinferred in hydration shells,26 may result from the operation ofother noncovalent forces rather constituting stabilizing forces inand of themselves.27

Supporting Information Available: NMR, IR, and crystallographicdata (9 pages, print/PDF). See any current masthead page for orderinginformation and Web access instructions.

JA981604U

(19) Borah, B.; Wood, J. L. Spectrochim. Acta 1977, 33A, 381.(20) Compound 3 displays an N-H stretch band at 3306 cm-1 in the solid

state. The previously reported crystal structure of this compound shows theNH to be involved in a 10-membered ring H-bond (HO ) 1.82 ,N-HO angle ) 168), with no additional intermolecular H-bonding:Lecomte, P. C.; Aubry, A.; Protas, J.; Boussard, G.; Marraud, M. ActaCrystallogr. 1974, B30, 1992.

(21) (a) Liang, G.-B.; Dado, G. P.; Gellman, S. H. J. Am. Chem. Soc. 1991,113, 3994. (b) Liang, G.-B.; Desper, J. M.; Gellman, S. H. J. Am. Chem. Soc.1993, 115, 925.

(22) (a) Peters, D.; Peters, J. J. Mol. Struct. 1980, 68, 255. (b) Mitchell, J.B. O.; Price, S. L. Chem. Phys. Lett. 1989, 154, 267.

(23) (a) Jorgensen, W. L.; Pranata, J. J. Am. Chem. Soc. 1990, 112, 2008.(b) Pranata, J.; Wierschke, S. G.; Jorgensen, W. L. J. Am. Chem. Soc. 1991,113, 2810. (c) Jeong, K. S.; Tjivikua, T.; Muehldorf, A.; Deslongchamps, G.;Famulok, M.; Rebek, J. J. Am. Chem. Soc. 1991, 113, 201. (d) Jorgensen, W.L.; Severance, D. L. J. Am. Chem. Soc. 1991, 113, 209.

(24) (a) Gardner, R. R.; Gellman, S. H. J. Am. Chem. Soc. 1995, 117, 10411.(b) Gardner, R. R.; Gellman, S. H. Tetrahedron 1997, 53, 9881.

(25) (a) Zimmerman, S. C.; Murray, T. J. Tetrahedron Lett. 1994, 35, 4077.(b) Murray, T. J.; Zimmerman, S. C.; Kolotuchin, S. V. Tetrahedron 1995,51, 635.

(26) Savage, H. J.; Elliot, C. J.; Freeman, C. M.; Finney, J. L. J. Chem.Soc., Faraday Trans. 1993, 89, 2609. For an opposing view, see: McDonald,I. K.; Thornton, J. M. J. Mol. Biol. 1994, 238, 777.

(27) We thank Dr. Douglas Powell for solving the crystal structure of 1.This work was supported by the National Science Foundation (CHE-9622653).

Communications to the Editor J. Am. Chem. Soc., Vol. 120, No. 35, 1998 9091